1. Field of the Invention
This invention relates to devices and methods for measuring the concentration of one or more analytes in a human body part. More specifically, this invention relates to devices and methods for the noninvasive determination of in vivo analyte concentrations under conditions of precise temperature control.
2. Discussion of the Art
Non-invasive optical monitoring of metabolites is an important tool for clinical diagnostics. The ability to determine an analyte, or a disease state, in a human subject without performing an invasive procedure, such as removing a sample of blood or a biopsy specimen, has several advantages. These advantages include ease of performing the test, reduced pain and discomfort, and decreased exposure to potential biohazards. The result will be increased frequency of testing, accurate monitoring and control, and improved patient care. Representative examples of non-invasive measurements include pulse oximetry for oxygen saturation (U.S. Pat. Nos. 3,638,640; 4,223,680; 5,007,423; 5,277,181; 5,297,548), laser Doppler flowmetry for diagnosis of circulation disorder (Toke et al, xe2x80x9cSkin microvascular blood flow control in long duration diabetics with and without complicationxe2x80x9d, Diabetes Research, Vol. 5, Pages 189-192, 1987), determination of tissue oxygenation (WO 92/20273), determination of hemoglobin (U.S. Pat. No. 5,720,284) and of hematocrit (U.S. Pat. Nos. 5,553,615; 5,372,136; 5,499,627; WO 93/13706).).
Measurements in the near-infrared spectral region are commonly proposed, or used, in prior art technologies. The 600-1100 nm region of the spectrum represents a window between the visible hemoglobin and melanin absorption bands and the infrared strong water absorption band. Light can penetrate deep enough in the skin to allow use in a spectral measurement or a therapeutic procedure.
Oximetry measurement is very important for critical patient care, especially after use of anesthesia. Oxygenation measurements of tissue are also important diagnostic tools for measuring oxygen content of the of the brain of the newborn during and after delivery and for sports medicine and tissue healing monitoring. Non-invasive determination of hemoglobin and hematocrit would offer a simple non-biohazardous painless procedure for use in blood donation centers, thereby increasing the number of donations by offering an alternative to the invasive procedure, which is inaccurate and could lead to rejection of a number of qualified donors. Hemoglobin and hematocrit values are useful for the diagnosis of anemia in infants and mothers, without the pain associated with pediatric blood sampling. Non-invasive determination of hemoglobin has been studied in the art as a method for localizing tumors and diagnosis of hematoma and internal bleeding. Non-invasive hematocrit measurements can yield important diagnostic information on patients with kidney failure before and during dialysis. There are more than 50 million dialysis procedures performed in the United Stated and close to 80 million procedures performed world-wide per year.
The most important potential advantage for non-invasive diagnostics possibly will for non-invasive diagnosis of diabetes. Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism characterized by an absolute or relative insulin deficiency, hyperglycemia, and glycosuria. At least two major variants of the disease have been identified. xe2x80x9cType Ixe2x80x9d accounts for about 10% of diabetics and is characterized by a severe insulin deficiency resulting from a loss of insulin-secreting beta cells in the pancreas. The remainder of diabetic patients suffer from xe2x80x9cType IIxe2x80x9d, which is characterized by an impaired insulin response in the peripheral tissues (Robbins, S. L. et al., Pathologic Basis of Disease, 3rd Edition, W. B. Saunders Company, Philadelphia, 1984, p. 972). If uncontrolled, diabetes can result in a variety of adverse clinical manifestations, including retinopathy, atherosclerosis, microangiopathy, nephropathy, and neuropathy. In its advanced stages, diabetes can cause blindness, coma, and ultimately death.
The principal treatment for Type I diabetes is periodic insulin injection. Appropriate insulin administration can prevent, and even reverse, some of the adverse clinical outcomes for Type I diabetics. Frequent adjustments of the blood glucose level can be achieved either by discrete injections or, in severe cases, via an implanted insulin pump or artificial pancreas. The amount and frequency of insulin administration is determined by frequent or, preferably, continuous testing of the level of glucose in blood (i. e., blood glucose level).
Tight control of blood glucose in the xe2x80x9cnormal rangexe2x80x9d, 60-120 mg/dL, is necessary for diabetics to avoid or reduce complications resulting from hypoglycemia and hyperglycemia. To achieve this level of control, the American Diabetes Association recommends that diabetics test their blood glucose five times per day. Thus, there is a need for accurate and frequent or, preferably, continuous glucose monitoring to combat the effects of diabetes.
Conventional blood glucose measurements in a hospital or physician""s office rely on the withdrawal of a 5-10 mL blood sample from the patient for analysis. This method is slow and painful and cannot be used for continuous glucose monitoring. An additional problem for hospitals and physician offices is the disposal of testing elements that are contaminated by blood.
Implantable biosensors have also been proposed for glucose measurement. (G. S. Wilson, Y. Zhang, G. Reach, D. Moatti-Sirat, V. Poitout, D. R. Thevenot, F. Lemonnier, and J.-C. Klein, Clin. Chem. 38, 1613 (1992)). Biosensors are electrochemical devices having enzymes immobilized at the surface of an electrochemical transducer.
Portable, xe2x80x9cminimally-invasivexe2x80x9d testing systems are now commercially available. These systems require the patient to stick themselves to obtain a drop of blood which is then applied to a disposable test strip containing coated reagents or an electrochemical test element.
Although the portable instruments that read the strips are relatively inexpensive ($100-$200), the cumulative cost to diabetics for the disposable strips is considerable. Compliance is another major problem for minimally invasive techniques. Finger sticks are painful and can result in infections, scarring, and nerve damage in the finger. Disposal of potentially biohazardous test strips and lancets is yet another problem with these systems.
xe2x80x9cNon-invasivexe2x80x9d (alternatively referred to herein as xe2x80x9cNIxe2x80x9d) glucose sensing techniques measure in-vivo glucose concentrations without collecting a blood sample. As defined herein, a xe2x80x9cnon-invasivexe2x80x9d technique is one that can be used without removing a sample from, or without inserting any instrumentation into, the tissues. The concept involves irradiating a vascular region of the body with electromagnetic radiation and measuring the spectral information that results from one of four primary processes: reflection, absorption, scattering, and emission. The extent to which each of these processes occurs is dependent upon a variety of factors, including the wavelength and polarization state of the incident radiation and the glucose concentration in the body part. Glucose concentrations are determined from the spectral information by comparing the measured spectra to a calibration curve or by reference to a physical model of the tissue under examination. Various categories of non-invasive glucose measurement techniques will now be described.
NI techniques that utilize the absorption of infrared radiation can be divided into three distinct wavelength regimes: Near-infrared (NIR), Mid-infrared (MIR) and Far-infrared (FIR). As defined herein, NIR involves the wavelength range from about 600 nm to about 1200 nm, MIR involves the wavelength range from about 1200 nm to about 3000 nm and FIR involves the wavelength range from about 3000 nm to about 25000 nm. As defined herein, xe2x80x9cinfraredxe2x80x9d (or IR) is taken to mean a range of wavelengths from about 600 nm to about 25000 nm.
U.S. Pat. Nos. 5,086,229; 5,324,979; and 5,237,178 describe non-invasive methods for measuring blood glucose level involving NIR radiation. In general, a blood-containing body part (e. g., a finger) is illuminated by one or more light sources, and the light that is transmitted through the body part is detected by one or more detectors. A glucose level is derived from a comparison to reference spectra for glucose and background interferants. The 600-1100 nm spectral region contains a portion of the hemoglobin and water absorption bands, which are several orders of magnitude more intense than glucose overtone absorption bands. Thus, errors in the measurement of hemoglobin absorption, water absorption, tissue scattering, and blood scattering will greatly affect the glucose signal measured in this spectral range. Determination of hemoglobin and study of the factors affecting the hemoglobin-related signal are important for the determination of glucose when spectral data generated in the NIR region are employed. Thus, in addition to the diagnostic value of hemoglobin and hematocrit determinations, these determinations are important for estimating the variability in non-invasive glucose measurements. The NIR spectral region has been used for determination of blood oxygen saturation, hemoglobin, hematocrit, and tissue fat content. It is also used for exciting and detecting compounds in photodynamic therapy.
The use of MIR radiation for NI glucose measurement has been described in U.S. Pat. Nos. 5,362,966; 5,237,178; 5,533,509; and 4,655,225. The principles of operation are similar to those described for NIR radiation, except that the penetration depth of the MIR radiation is less than that of NIR radiation. As a consequence, most measurements in this region have been performed using a backscattering geometry. As defined herein, a xe2x80x9cbackscattering geometryxe2x80x9d describes a configuration wherein scattered radiation is collected on the same side of the sample as the entry point of the incident radiation. A xe2x80x9ctransmission geometryxe2x80x9d describes a configuration wherein light is transmitted through the sample and collected on the side of the sample opposite to the entry point of the incident radiation. This spectral region is less useful for the determination of hemoglobin and hematocrit. However the 1300-1390 nm wavelength has been used as a reference and water absorption wavelength for hematocrit determination.
FIR measurements have been described in U.S. Pat. Nos. 5,313,941; 5,115,133; 5,481,113; 5,452,716; 5,515,847; 5,348,003; and DE4242083.
The photoacoustic effect results from the absorption of a pulse of optical energy by tissues of a test subject, which optical energy is rapidly converted into thermal energy. The subsequent thermal expansion generates an acoustic pressure wave, which is measured by an acoustic transducer. In addition to the absorption of light, the measured photoacoustic signal depends upon the speed of sound in the medium, the thermal expansion coefficient, and the specific heat of the medium.
Glucose measurements employing the photoacoustic effect have been described by Quan et al. (K. M. Quan, G. B. Christison, H. A. MacKenzie, P. Hodgson, Phys. Med. Biol., 38 (1993), pp. 1911-1922) and U.S. Pat. No. 5,348,002.
Methods for the determination of glucose concentrations using changes in the polarization of light are described WO 92/10131, WO 93/07801, WO 94/02837, WO 94/05984, and WO 94/13199 and U.S. Pat. Nos. 4,882,492; 5,086,229; 5,209,231; 5,218,207; 5,321,265; 5,337,745; 5,361,758; and 5,383,452.
An electromagnetic wave incident on an isolated molecule with an electron cloud will cause the electrons to oscillate about their equilibrium positions, in synchrony with the applied wave. The resulting electronic oscillator instantaneously emits radiation (scatters) in all directions in a plane perpendicular to the oscillating electrons. Most of the scattered photons are elastically scattered, i. e., they have the same frequency as the incident radiation. A small fraction of the scattered light (less than one in a thousand incident photons) is inelastically (Raman) scattered. Unless otherwise indicated herein, xe2x80x9cscatteringxe2x80x9d refers to elastic scattering.
Because of the multiple scattering effect of tissue, optical measurements, whether in transmission or reflectance, will contain tissue scattering information, as well as absorption information. Tissue scattering information includes cell size and cell shape, depth of layers and refractive index of intracellular fluids and extracellular fluids. Absorption information includes absorption by visible components, such as hemoglobin, melanin, and bilirubin, and the overtone absorption of water, glucose, lipids, and other metabolites.
Spatially resolved light scattering (SRLS) techniques are a subset of the elastic scattering methods previously described. As shown in FIG. 1, light is injected into the surface of a tissue sample, such as a body part, at an injection point. The diffusely reflected light, R, is measured at two or more detection points located on the sample surface (e. g., the skin) at different detector distances, r, from the injection point. The dependence of the intensity of the diffuse reflectance R as a function of the detector distance (r) is used to derive scattering and absorption coefficients of the tissue sample. These coefficients, in turn, are related to the concentration of analyte(s). SRLS techniques have been described U.S. Pat. Nos. 5,551,422; 5,676,143; 5,492,118; 5,057,695, European Patent Application EP 0810429, and in the journal literature (B. Chance, H. Liu, T. Kitai, Y. Zhang, Analytical Biochemistry, 227, 1995, pp. 351-362. H. Liu, B. Beauvoit, M. Kimura, B. Chance, Journal of Biomedical Optics, 1(2), April, 1996, pp. 200-211. J. Qu, B. Wilson, Journal of Biomedical Optics, 2(3), July 1997, pp. 319-325; A. Kienle, L. Lilge, M. Patterson, R. Hibst, R. Steiner, B. Wilson, Applied Optics, 35(13), May 1996, pp. 2304-2314.
Frequency-domain reflectance measurements use optical systems similar to those used for spatially resolved light scattering (R as a function of r), except that the light source and the detector are modulated at a high frequency (U.S. Pat. Nos. 5,187,672; 5,122,974). The difference in phase angle and modulation between injected and reflected beam is used to calculate the reduced scattering coefficient and the absorption coefficient of the tissue or turbid medium. U.S. Pat. No. 5,492,769 describes frequency domain method and apparatus for the determination of a change in the concentration of an analyte, and U.S. Pat. No. 5,492,118 describes a method and apparatus for determination of the scattering coefficient of tissues.
U.S. Pat. No. 5,553,616 describes the use of Raman scattering with NIR excitation and an artificial neural network for measuring blood glucose level. Although glucose Raman bands are distinct from protein Raman bands, sensitivity of this method limits its applicability for in-vivo measurements. WO 92/10131 discusses the application of stimulated Raman spectroscopy for detecting the presence of glucose.
The NI techniques described above are painless, reagentless, and are expected to be less expensive than the finger stick approach over the long term use by a patient. NI techniques also eliminate the potentially biohazardous waste associated with invasive and minimally invasive measurements. However, NI methods have not yet achieved the level of accuracy and precision that is required for measuring physiologically relevant concentrations of glucose in-vivo.
A major challenge for all of the non-invasive techniques to date has been to collect spectral information with sufficiently high signal-to-noise ratios to discriminate weak glucose signals from the background noise. In the ideal case, a non-invasive sensor would be highly sensitive for the parameter of interest (e. g., glucose concentration) while remaining insensitive to interfering analytes or physiological parameters. In practice, all of the non-invasive measurement techniques described in the prior art are sensitive to one or more interfering xe2x80x9cphysiologicalxe2x80x9d or xe2x80x9cspectralxe2x80x9d variables.
As used herein, the expression xe2x80x9cphysiological variablesxe2x80x9d describes physiological parameters, such as temperature, that can adversely affect the sensitivity or selectivity of a non-invasive measurement. As used herein, the expression xe2x80x9cspectral variablesxe2x80x9d describes spectral features that arise either from poorly resolved analyte bands or from other interfering components in the sample. Several significant sources of spectral interference for the NI determination of glucose in biological samples are water, hemoglobin, albumin, cholesterol, urea, etc. Other tissue constituents that are present at lower concentrations or have lower absorption or scattering cross-sections may also contribute to an overall background signal that is difficult to separate.
Physiological and spectral variables can introduce unwanted noise, or worse, completely overwhelm the measured signals of interest (e. g., those related to glucose concentration). It is difficult to eliminate these interferences because they may exhibit one or more of the following properties:
(a) they may contribute nonlinearly to the measured signal,
(b) they may vary with spatial location within the sample,
(c) they may vary over time, or
(d) they may vary from sample to sample.
Co-pending U.S. application Ser. No. 08/982,939, filed Dec. 2, 1997, assigned to the assignee of this application, describes a multiplex sensor that combines at least two NI techniques selected from those described above in order to compensate for the effects of spectral and physiological variables. A description of prior art measurements in which tissue temperature is controlled is provided below.
U.S. Pat. Nos. 3,628,525; 4,259,963; 4,432,365; 4,890,619; 4,926,867; 5,131,391, and European Patent Application EP 0472216 describe oximetry probes with heating elements that are placed against a body part. These devices enhance sensitivity of the oximeter by elevating local tissue perfusion rates, thereby increasing hemoglobin concentrations. U.S. Pat. No. 5,148,082 describes a method for increasing the blood flow in a patient""s tissue, during a photoplethsmography measurement, by warming the tissue with heat generated by a semiconductor device mounted in a sensor. The heating element comprises a less efficient photodiode that acts as a heat source and as a light source.
U.S. Pat. No. 5,551,422 describes a glucose sensor that is xe2x80x9cbrought to a specified temperature preferably somewhat above normal body temperature (above 37xc2x0 C.) with a thermostatically controlled heating systemxe2x80x9d. Unlike the oximetry sensors, simply increasing tissue perfusion without controlling it is contraindicated for glucose measurements, because hemoglobin interferes with glucose measurement. This patent also fails to account for large variations in scattering intensity that result from the temperature gradient between the skin surface and the interior of the body part. As will be described more thoroughly below, the smallest devices disclosed in that patent have an average sampling depth of 1.7 mm. Depths and lateral distances of several millimeters are sampled at the longest spacings between source and detector taught in that patent. As shown in FIG. 1 and as defined herein, the average sampling depth, dav, is the average penetration depth along an axis normal to the tissue surface that is sampled in a given NI measurement. A thermal model of the human forearm, shown in FIGS. 6-8, suggests that, depending on the ambient temperature, the temperature of the tissue at a depth of 1.7 mm could be as much as 0.5xc2x0 C. warmer than that of the skin surface. According to Wilson et al., (J. Qu, B. Wilson, Journal of Biomedical Optics, 2(3), July 1997, pp. 319-325), the change in scattering expected for a 0.5xc2x0 C. change in temperature is equivalent to a 5 mM (90 mg/dL) change in glucose concentration. Thus, the scattering variability due to the temperature gradient probed by U.S. Pat. No. 5,551,422 is as large as the signal expected for normal physiological glucose levels.
Although a variety of spectroscopic techniques are disclosed in the prior art, there is still no commercially available device that provides noninvasive glucose measurements with an accuracy that is comparable to invasive methods. All of the prior art methods respond to glucose concentrations, but they are also sensitive to physiological and spectral variables. As a result, current approaches to non-invasive glucose testing have not achieved acceptable precision and accuracy.
Thus, there is a continuing need for improved NI instruments and methods that are unaffected by variations in tissue such as temperature and perfusion. There is also a need for improved NI instruments and methods that will provide essentially the same accuracy as conventional, invasive blood glucose tests. There is also a need for low-cost, reagent-free, painless, and environmentally friendly instruments and methods for measuring blood glucose levels in diabetic or hypoglycemic patients.
In one aspect, the present invention involves devices and methods for non-invasively measuring at least one parameter of a sample, such as the presence or concentration of an analyte, in a body part wherein the temperature is controlled. As will be described more fully below, the present invention measures light that is reflected, scattered, absorbed, or emitted by the sample from an average sampling depth, dav, that is confined within a temperature controlled region in the tissue. This average sampling depth is preferably less than 2 mm, and more preferably less than 1 mm. Confining the sampling depth into the tissue is achieved by appropriate selection of the separation between the light introduction site and the light collection site and the illumination wavelengths.
Confining the sampling depth provides several advantages. First, the entire signal is acquired from a region of tissue having a substantially uniform temperature. As defined herein, a xe2x80x9csubstantially uniform tissue temperaturexe2x80x9d means that the temperature of the tissue varies by no more than xc2x10.20xc2x0 C., preferably no more than xc2x10.1xc2x0 C. Secondly, the sampled tissue region is more homogeneous than the tissue regions sampled by the devices of the prior art. As a result, physiological and spectral interferences are controlled so that their contributions may be separated, quantified, and removed from the signals of interest.
In the present invention, the area of the skin of the body part where temperature is controlled is larger than the optical sampling area. A preferred ratio of the area of controlled temperature (surface area of the temperature controlled body interface) to the optical sampling area (surface area of the optical probe) is greater than 2:1, preferably greater than 5:1.
In another aspect, the present invention involves a method and apparatus for non-invasively measuring at least one parameter of a body part with temperature stepping. As defined herein, xe2x80x9ctemperature steppingxe2x80x9d comprises changing the temperature of a tissue sample between at least two different predefined temperatures. Non-invasive measurements are performed at each of the two or more different temperatures in order to remove the effects of temperature fluctuations on the measurement.
In another aspect, the present invention involves a method and apparatus for non-invasively measuring at least one parameter of a body part with temperature modulation. As used herein, temperature modulation consists of cycling the temperature (changing the temperature repeatedly) between at least two different predefined temperatures. Non-invasive measurements are performed at each of the two or more different temperatures in order to eliminate the effects of temperature fluctuations on the measurement.
In another aspect, the present invention provides an improved method of measuring at least one parameter of a tissue sample comprising the steps of:
(a) lowering the temperature of said tissue sample to a temperature that is lower than the normal physiological temperature of the body; and
(b) determining at least one optical property of said tissue sample.
In another aspect, the present invention provides a method of measuring at least one parameter of a tissue sample comprising the steps of:
(a) stepping the temperature of said tissue sample between at least two different temperatures;
(b) measuring said at least one optical property of the tissue sample as a function of temperature;
(c) computing the change in the at least one optical property as a function of change in temperature; and
(d) correlating the at least one parameter of the tissue sample with the functional dependence of the at least one optical property on temperature.
The present invention is particularly advantageous for biological samples where multiple interfering analytes or physiological variables can affect the measurement. Non-invasive measurements may be made on a body part of a patient, e. g., a finger, earlobe, lip, toe, skin fold, or bridge of the nose.
The invention offers several advantages over the prior art. At small separations of light introduction site from light collection site, light samples penetrate the tissue to a lower depth, where smaller temperature gradients are encountered, than to deeper regions of the tissue. In addition, better temperature control can be achieved at lower depths of penetration in the sampled region. If the separation of light introduction site from light collection site varies over large distances (e. g., 0.5 cm-7 cm), light from the light introduction site and collected light propagates through the epidermis, the dermis, as well as deeper regions of tissue, including the subcutis (which has higher fatty adipose tissue content) and underlying muscle structures. These layers provide sources of variability in measurements because of the difference in cell size, cell packing, blood content, as well as thermal properties.
In addition, for tissue that is heterogeneous along dimensions parallel to the skin surface (x and y), there is lower likelihood of photons encountering tissue components that will cause anomalies in the scattering measurements. It is also possible to perform measurements on a small localized area of the skin with a probe design having a closely spaced light introduction site and light collection site than with a light introduction site that is located a great distance from the light collection site. Thus, it is possible to detect blood vessels and hair fibers and determine their effect on the signal.
Probes having large separations of light introduction site from light collection site require the use of a large body mass, such as the muscle of the arm, thigh, or the abdomen. Accordingly, the body site locations where such a probe can be used on are limited, and substantial disrobing and inconvenience for the user is required. Thus, another advantage of the probe design of the present invention is that probes of 5 mm or less can be used, particularly with small body parts, such as ear lobes and fingers. However, probes of 5 mm or less can also be used with larger body parts, such as the forearm, thigh, or abdomen.
Another advantage of a small separation between light introduction site and light collection site is the higher signal to noise ratio obtainable at small separations due to increases in the amount of light reaching the light collection site. Thus simpler, inexpensive, rugged components, such as light emitting diodes, small flash lamps, and incandescent lamps, can be used as light sources, and commercially available inexpensive photodiodes can be used as detectors. Probes having a large separation between light introduction site and light collection site use laser diodes and photomultiplier tubes, because weaker signals are generated.
In addition to convenience and cost advantages, other engineering design considerations favor the probe design of the present invention. It is preferred to generate a constant temperature using standard Peltier cooler elements that are approximately 1 cm squares. In order to obtain an aspect ratio of 5/1, probes of 2 mm or less are desirable, especially for use with small body parts, such as ear lobes and fingers. Larger thermoelectric cooling and heating elements may be employed at a cost of higher power consumption and greater heat dissipation.
Prior art measurements that use separations of light collection site and light introduction site in excess of 3 mm result in the phase and polarization of the incident light that are randomized. However, in the present invention, the preferred separations are less than 2 mm, and polarization and interference effects can be measured. The use of polarizers and polarization conserving fibers can reveal some internal sample properties. In addition, temperature effects on transmission of polarized light through tissue can be studied with the apparatus of the present invention.